Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling.

Kassandra Kisler,Angeliki M Nikolakopoulou,Divna Lazic,Berislav V Zlokovic,Melanie D Sweeney,Zhen Zhao

doi:10.3389/fncel.2020.00027

Kassandra Kisler, Angeliki M Nikolakopoulou + Show 4 more

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https://doi.org/10.3389/fncel.2020.00027

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Abstract

Pericytes are perivascular mural cells that enwrap brain capillaries and maintain blood-brain barrier (BBB) integrity. Most studies suggest that pericytes regulate cerebral blood flow (CBF) and oxygen delivery to activated brain structures, known as neurovascular coupling. While we have previously shown that congenital loss of pericytes leads over time to aberrant hemodynamic responses, the effects of acute global pericyte loss on neurovascular coupling have not been studied. To address this, we used our recently reported inducible pericyte-specific Cre mouse line crossed to iDTR mice carrying Cre-dependent human diphtheria toxin (DT) receptor, which upon DT treatment leads to acute pericyte ablation. As expected, DT led to rapid progressive loss of pericyte coverage of cortical capillaries up to 50% at 3 days post-DT, which correlated with approximately 50% reductions in stimulus-induced CBF responses measured with laser doppler flowmetry (LDF) and/or intrinsic optical signal (IOS) imaging. Endothelial response to acetylcholine, microvascular density, and neuronal evoked membrane potential responses remained, however, unchanged, as well as arteriolar smooth muscle cell (SMC) coverage and functional responses to adenosine, as we previously reported. Together, these data suggest that neurovascular uncoupling in this model is driven by pericyte loss, but not other vascular deficits or neuronal dysfunction. These results further support the role of pericytes in CBF regulation and may have implications for neurological conditions associated with rapid pericyte loss such as hypoperfusion and stroke, as well as conditions where the exact time course of global regional pericyte loss is less clear, such as Alzheimer’s disease (AD) and other neurogenerative disorders.

Highlights

Proper brain functioning depends on delivery of oxygen and nutrients via cerebral blood flow (CBF)
Analysis of CBF responses to hind-limb stimulation as measured by laser doppler flowmetry (LDF) in the S1 cortex hind-limb region in TAM-treated pericyte-CreER; iDTR mice revealed progressive neurovascular dysregulation beginning with a 36% reduction in CBF response at day 6 of diphtheria toxin (DT) treatment compared to vehicle, and reaching 57% reduction in CBF response at 3 days post-DT compared to vehicle (Figure 1D)
Using our recently developed pericyte-specific Cre line crossed to iDTR mice (Nikolakopoulou et al, 2019), we found that deficits in neurovascular coupling develop rapidly after global pericyte ablation from the cortex of adult mice

Summary

Introduction

Proper brain functioning depends on delivery of oxygen and nutrients via cerebral blood flow (CBF). While we have previously shown that moderate loss of pericytes in Pdgfrb pericyte-deficient mice leads to neurovascular uncoupling and diminished oxygen delivery preceding late-appearing neuronal changes (Kisler et al, 2017b), it is not clear if any developmental compensation occurred in this model that might contribute to aberrant neurovascular coupling. Using an in vivo laser ablation technique, another study has shown that acute single pericyte ablation leads to localized temporary loss of vascular tone and capillary dilation (Berthiaume et al, 2018) Neither of these studies examined the effect of the rapid and global loss of brain pericytes on hemodynamic responses, as it may occur in some acute and chronic neurological disorders (Sweeney et al, 2018a,b, 2019)

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